Dectin-1 and DC-SIGN Polymorphisms Associated with Invasive Pulmonary Aspergillosis Infection

Abstract

The recognition of pathogen-derived structures by C-type lectins and the chemotactic activity mediated by the CCL2/CCR2 axis are critical steps in determining the host immune response to fungi. The present study was designed to investigate whether the presence of single nucleotide polymorphisms (SNPs) within DC-SIGN, Dectin-1, Dectin-2, CCL2 and CCR2 genes influence the risk of developing Invasive Pulmonary Aspergillosis (IPA). Twenty-seven SNPs were selected using a hybrid functional/tagging approach and genotyped in 182 haematological patients, fifty-seven of them diagnosed with proven or probable IPA according to the 2008 EORTC/MSG criteria. Association analysis revealed that carriers of the Dectin-1 rs3901533 T/T and Dectin-1 rs7309123 G/G genotypes and DC-SIGN rs4804800 G, DC-SIGN rs11465384 T, DC-SIGN 7248637 A and DC-SIGN 7252229 C alleles had a significantly increased risk of IPA infection (OR = 5.59 95%CI 1.37–22.77; OR = 4.91 95%CI 1.52–15.89; OR = 2.75 95%CI 1.27–5.95; OR = 2.70 95%CI 1.24–5.90; OR = 2.39 95%CI 1.09–5.22 and OR = 2.05 95%CI 1.00–4.22, respectively). There was also a significantly increased frequency of galactomannan positivity among patients carrying the Dectin-1 rs3901533_T allele and Dectin-1 rs7309123_G/G genotype. In addition, healthy individuals with this latter genotype showed a significantly decreased level of Dectin-1 mRNA expression compared to C-allele carriers, suggesting a role of the Dectin-1 rs7309123 polymorphism in determining the levels of Dectin-1 and, consequently, the level of susceptibility to IPA infection. SNP-SNP interaction (epistasis) analysis revealed significant interactions models including SNPs in Dectin-1, Dectin-2, CCL2 and CCR2 genes, with synergistic genetic effects. Although these results need to be further validated in larger cohorts, they suggest that Dectin-1, DC-SIGN, Dectin-2, CCL2 and CCR2 genetic variants influence the risk of IPA infection and might be useful in developing a risk-adapted prophylaxis.

Massively parallel targeted resequencing reveals novel genetic variants associated with aspergillosis in paediatric patients with haematological malignancies

“…It is also worth noting that gene regulation is often influenced by epistatic interactions. Possibility of SNP-SNP epistasis in invasive aspergillosis was actually suggested for selected variants of CLEC7A, CCL2 and CCR2 [34]. Overall, the findings of this and other studies contribute to our understanding of the complicated nature of potential susceptibility to aspergillosis, underlining the importance of non-canonical splicing, gene regulation and gene-gene interactions.…”

Validation of single nucleotide polymorphisms in invasive aspergillosis following hematopoietic cell transplantation

“…[7][8][9][10][11][12][13][14][15][16][17][18] However, the majority of these studies were not validated independently, and sometimes the results of a study conflict with those of other studies. For example, although associations with Dectin-1/ CLEC7A and IA have been reported in some studies (Table 1), 8,9 Chai et al 19 found no association in their study. Additionally, the studies examined small patient cohorts and, at most, several SNPs simultaneously.…”

Polymorphisms in Host Immunity-Modulating Genes and Risk of Invasive Aspergillosis: Results from the AspBIOmics Consortium

“…SNP selection was based on three criteria: (i) SNPs within immunoregulatory genes that may affect immune responses, (ii) SNPs having laboratory evidence of a biological function, and/or (iii) SNPs previously reported as being associated with infectious diseases (Table 1). SNPs were genotyped using KASPar assays (LGC Genomics KBioscience, London, United Kingdom) as previously described in detail (28). Patients were included either if they were undergoing allo-HSCT or if they had been diagnosed with acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL) and were receiving intensive remission-induction chemotherapy.…”

“…The remarkable genetic variation of immune genes suggests that the presence of specific genetic variants in these genes influences their biological functions and, consequently, affect the risk of developing invasive fungal infections, such as IA. In support of this hypothesis, recent studies on genetic susceptibility have successfully identified several genetic variants on PRR genes (DC-SIGN, Dectin-1, TLRs, PTX3, and MBL) (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), cytokines (IL1 gene cluster, IL10, IL12, and IFN␥) (32,(41)(42)(43)(44), chemokines (CXCL10) (45), and immune receptors (TNFR1 and TNFR2) (46,47) as factors influencing the risk of developing IA. With this background, the purpose of this study was to comprehensively assess whether the presence of single-nucleotide polymorphisms (SNPs) within 14 immune-modulating genes (IL4, IL4R, IL8, IL8RA, IL8RB, IL10, IL12A, IL12B, IL13, IFN␥, IFN␥R2, CCR5, MIF, and VEGF) influence the risk of developing IA.…”